Hepatitis B infection and immunity in migrant children and pregnant persons in Europe: a systematic review and meta-analysis

Abstract Background The WHO’s global hepatitis strategy aims to achieve viral hepatitis elimination by 2030. Migrant children and pregnant persons represent an important target group for prevention strategies. However, evidence on the burden of chronic hepatitis B (CHB) infection and the factors affecting its incidence is lacking. Methods EMBASE, Global Health, Global Index Medicus, Web of Science and Medline were searched for articles in any language from 1 January 2012 to 8 June 2022. Studies reporting CHB prevalence, disease severity, complications and/or prevention strategies, including vaccination, prevention of vertical transmission and access to care/treatment for migrant children and pregnant migrants, were included. Pooled estimates of CHB prevalence and hepatitis B vaccination (HBV) coverage among migrant children were calculated using random effects meta-analysis. Findings 42 studies were included, 27 relating to migrant children and 15 to pregnant migrants across 12 European countries, involving data from 64 773 migrants. Migrants had a higher incidence of CHB than host populations. Among children, the pooled prevalence of CHB was higher for unaccompanied minors (UAM) (5%, [95% CI: 3–7%]) compared to other child migrants, including internationally adopted children (IAC) and refugees (1%, [95% CI: 1–2%]). Region of origin was identified as a risk factor for CHB, with children from Africa and pregnant migrants from Africa, Eastern Europe and China at the highest risk. Pooled estimates of HBV vaccine coverage were lower among UAM (12%, [95% CI: 3–21%]) compared to other child migrants (50%, [95% CI: 37–63%]). Conclusion A range of modifiable determinants of HBV prevalence in migrant children and pregnant persons were identified, including sub-optimal screening, prevention and continuum of care. There is a need to develop evidence-based approaches in hepatitis care for these groups, thereby contributing towards global viral hepatitis elimination goals.


Introduction
Chronic hepatitis B (CHB) is defined as the persistence of hepatitis B surface antigen (HBsAg) for 6 months or more after acute infection with hepatitis B virus (HBV). 1 There are an estimated 296 million people living with CHB globally, 2 including 6 million children younger than 5 years. 3The majority live in highly endemic areas (where the prevalence of CHB is >8% of the population), including the East Asian, Eastern Mediterranean, Western Pacific and African regions. 4In these areas, most infections occur during infancy or childhood due to vertical transmission (mostly during childbirth but occasionally during pregnancy) 5 or due to horizontal household transmission between children. 6The risk of progression from acute to chronic infection is higher when infection occurs in younger age groups, compared to populations who are infected later in life.Progression rates can reach up to 90% when infection occurs in the neonatal period, compared to 20% in childhood, and <5% in immunocompetent adults. 7 -9In 2019, 820 000 deaths were attributable to CHB globally, many of which were secondary to cirrhosis and hepatocellular carcinoma (HCC). 10he sustainable development goals highlighted the importance of combatting hepatitis, and in 2016, the WHO launched a global strategy for achieving viral hepatitis elimination as a public health threat by 2030, 2 defined as a 90% reduction in incidence and a 65% reduction in mortality compared with the 2015 baseline. 2Paediatric and vaccine-specific targets included 90% coverage of the 3-dose vaccine regimen and reducing HBsAg in children under 5 years to <0.1%. 11It also forms part of the triple elimination initiative, which aims to synergise efforts to prevent mother-to-child transmission of HIV, HBV and syphilis. 125][16] Global coverage with three doses of the hepatitis B vaccine is estimated to be at 84%, 17 with a target rate of 90% by 2030. 10 Progress towards this fast-approaching WHO global deadline has been unequal across high burden populations.In Europe, a region with low endemicity that has seen recent migration waves from high (>8%) and intermediate (2-7%) CHB endemic regions, 4 migrant populations are at higher risk of CHB than the native-born population, 18,19 and migrants from countries where CHB is highly prevalent (≥2%) account for 25% of all CHB infections in the EU. 20Migrant children and pregnant persons in Europe are thus an important area of focus for regional prevention and care programmes. 19][23] This has resulted in migrants being under-immunised for hepatitis B and other communicable diseases. 21Although all 31 EU/EEA countries recommend vaccination for children in highrisk groups, and 27 even recommend universal childhood HBV vaccination, only seven EU/EEA countries have a national policy for screening migrants specifically for HBV. 24With regards to antenatal screening for HBV, universal screening is national policy in seven EU/EAA countries, and opt-out screening is policy in a further 14. 25 Migrant children and pregnant persons are not only a key at risk group for CHB but are also cared for within distinct healthcare pathways and services (i.e.antenatal care, paediatric clinics and childhood vaccination services) within which HBV prevention and treatment could potentially be more easily administered.This includes opportunities to deliver prevention, most notably HBV vaccination, opportunistically if flexibility exists around the commissioning of these services.A strong evidence base is therefore vital for curating informed and tailored interventions for the prevention of CHB in these specific vulnerable groups.While evidence on the prevalence of CHB in migrants has previously been the subject of systematic reviews, there is currently no evidence synthesis available on CHB in migrant children and pregnant persons specifically. 26,27

Methods
We conducted a systematic review and meta-analysis, according to PRISMA guidelines,28 to determine CHB prevalence, disease severity and complications and factors affecting incidence, including primary and secondary prevention strategies (vaccination, prevention of vertical transmission, screening and access to care/treatment, respectively) among migrant children and pregnant migrant populations in Europe.

Inclusion and exclusion criteria
The inclusion and exclusion criteria were developed using the Joanna Briggs Institute methodology 29 (Appendix Table AA1, p. 1).We included primary research studies with data on CHB prevalence (primary outcome) and disease severity/complications and factors affecting CHB incidence, including vaccination status, prevention of vertical transmission, screening and access to care/treatment (secondary outcomes), among migrant pregnant women and/or children aged 18 years or less born outside the country of study and living in the EU, EEA, UK and Switzerland (i.e.first generation migrants) in all migrant groups (Appendix Box 1, p. 2).Observational studies, case reports and systematic reviews were included, and comments/editorials, conference abstracts and modelling studies were excluded.Studies published before 2012 were excluded to ensure that the evidence obtained was consistent with current migration trends and CHB prevention approaches, such as global vaccination recommendations.

Search strategy and study selection
We searched EMBASE, Global Health, Global Index Medicus, Web of Science and Medline for primary research articles in any language published from 1 January 2012 to 8 June 2022 combining English-language keyword search terms and medical subject headings using Boolean operators relating to migrants, prevalence, Hepatitis B and Europe (Appendix Figure AA1, pp.2-5).Grey literature of relevant governmental and nongovernmental organisations [e.g.WHO, European Centre for Communicable Disease Control (ECDC)] was consulted.Bibliographies of the included studies were hand-searched for additional relevant studies.
Google was searched with key terms (including 'migrant', 'Hepatitis B' and 'Europe') and the first 50 results were reviewed.No language restrictions were applied, and Google translate and DeepL translator were used as required. 30,31ta screening, extraction and synthesis Records were imported into EndNote and duplicates were deleted.Title, abstract and full-text screening were carried out according to the aforementioned inclusion and exclusion criteria.Data were extracted and tabulated separately for migrant children and pregnant women.Using Microsoft Excel, a standardised form was developed to extract data on the following: author and year of publication of study, study setting and location, study design, number of participants (where relevant), refugee and migrant demographics (country of origin, legal status), age group and gender (for children), CHB prevalence, disease severity or complications, HBV vaccination status/coverage, screening and access to CHB care services.
To estimate the pooled CHB prevalence and pooled HBV vaccine coverage among migrant children, we conducted metaanalyses using the random effects model available from Stata 17 metaprop function. 32This enabled the calculation of 95% confidence intervals using the statistical score and the exact binomial method, and it incorporated the Freeman-Tukey arcsine double proportions transformation. 33This method also models intra-study variability using the binomial distribution.Interstudy heterogeneity was described using the I2 statistic, which describes the percentage of variation across studies that is due to heterogeneity rather than chance.The weights of the studies were also calculated to account for the differing sample sizes of the studies.We calculated separate pooled estimates for unaccompanied minors (UAM) and children with other migration statuses, including those described as migrants, refugees, asylum seekers and international adopted children (IAC).We excluded studies where sample sizes were not specified or where prevalence data for UAM and other migration types were not disaggregated.Two studies that included data on young people aged 0-20 and 13-25 years were included. 34,35he risk of bias was assessed for all studies was carried out using the Newcastle-Ottawa scoring (NOS) system (score out of 9) and an adapted scoring system for cross-sectional studies (score out of 8).Studies that scored a total of 8 or 9 points were considered to have a low risk of bias; 7 or 6 points were considered to have a medium risk of bias; and 5 points or less were considered to have a high risk of bias.
Most studies (39/42) were cross-sectional and described the experiences of single centres and therefore consisted of nonrepresentative samples of migrants.7][38] All studies reported either on paediatric or pregnant migrants except for one study that reported on pregnant UAM 39 (Appendix Table A2, p. 5).
Risk of bias scores ranged from 3 to 8, with one study having a low risk of bias, 13 having a medium risk of bias and 28 having a high risk of bias (Appendix Table A3, pp.6-7).

Child migrants
Prevalence.The prevalence of CHB among migrant children reported in 23 studies ranged from 0 to 13% (Table 1 in the article and Appendix Table A4, pp.7-8).The prevalence varied according to several factors, including migrant type and country of origin.The pooled prevalence of CHB among UAMs was higher (5% [95% CI 3-7]) than among children with other migration statuses, including those described as migrants, refugees, asylum seekers and IAC (2% [95% CI 1-3]) (Figure 3A and B).
One study in France reported a particularly high prevalence of CHB (12.8%) among young people who self-identified as UAM, predominantly from West Africa, but not recognised by the state as such. 40By contrast, CHB was rarely identified among the IAC. 41 ,42n terms of country of origin, a Spanish study looking at prevalence of CHB among 350 migrant children found that all cases were from the WHO Africa Region and that there were no cases among North African and Latin American migrants. 43his finding was corroborated in a study describing CHB in UAM in Italy, where children from Gambia and Ivory Coast were found to have a higher prevalence compared to those from Libya. 44Paediatric CHB cases were also older (mean age 14.6) compared to vaccinated and non-immune cases (mean ages 11.2 and 11.5, respectively) and more likely to be male in a Spanish study of migrant children from Africa and Latin America and a German sample of UAM seeking asylum. 43,45sease severity and complications.One small Irish study in a clinic for children born to HBV-infected mothers reported complications of CHB-finding fibrosis or inflammation in 7% (4/63) of migrant children living with HBV who originated from Africa, Central Asia and Eastern Europe. 46Two studies, one in UAM, reported that the majority (75-93%) of infected children were negative for Hepatitis B e-antigen (HBeAg)-a marker of active    (Continued)   HBV replication and high infectivity. 47,48Most also had low viral loads, but the range of viremia differed substantially, and treatment status prior to assessment was not reported. 48Antiviral use was reported in studies from Germany in 2/8 adolescents and Ireland, in 3/57 children. 45,46ctors affecting CHB incidence Vaccination status and susceptible population.44][45][49][50][51][52][53][54] Pooled vaccine coverage estimates were lower among UAMs (12% [95% CI 3-21]) than among other migration categories, including those described as migrants, refugees, asylum seekers and IAC (50% [95% CI 37-63]) (Figure 4A and B).
The association between migrant type and vaccine coverage was also assessed in a Greek study, which found significantly (P = 0.015) lower coverage among refugees (defined as asylum seekers and irregular migrant children) compared to immigrants (defined as children of parents with long-term residence permits or those who entered for family reunification). 49accination coverage estimates were below coverage rates across most WHO regions in all studies (Figure 2 and Appendix Table A5, pp.10-11). 35 ,52Studies also noted that for most children (58.1-79.3%),vaccination records were unavailable, and when available, discrepancies frequently existed between documentation and serological evidence of HBV protection. 41,42reening and care pathways.Eighteen studies from Germany, 39 ,45,48,52,54-56 Spain, 34,43,57 Switzerland, 58 Italy, 41 ,42,44 France, 59 Greece, 49 Finland 47 and the UK, 60 reported having paediatric migrant health screening processes on arrival.However, target populations were not always reached, with a Finnish study reporting one-third of asylum seekers not being reached and some experiencing delays in screening. 47his was also noted in a UK study, where a median delay of 6 months between arrival in the UK and infection screening was observed. 60A Swiss hospital-based study reported the absence of routine screening procedures in refugee and asylum-seeking inpatient children and the incomplete administration of catchup immunisations. 58Retention in care was also a challenge, with six studies following UAM highlighting a high number of individuals who had tested HBV-positive being lost to followup due to rapid relocations, 54,61 communication barriers and logistical difficulties in accessing care. 48,53,60,61
Prevalence variation by region of origin was described in an Italian study and found to be highest among pregnant women from the Western Pacific Region, Eastern Europe and Africa (7.0%, 4.0% and 3.3%, respectively). 68In this study, more than half (60.6%) of the HBsAg positive pregnant women originated from China and Albania. 68Prevalence differences between migrants from specific geographical areas and host populations were examined in two studies. 68,70These established CHB prevalences were significantly higher in pregnant women from China (8.1%), Albania (7.7%), Ukraine (7.2%) and Senegal (6.1%) compared to Italian women (P < 0.05) 68 and in Southeast Asian (primarily Chinese) women (10.8%) compared to native Spanish women (P < 0.005). 70HB prevalence estimates by region of origin of pregnant migrants were collated from seven studies.High prevalence estimates (>8%) were found among pregnant migrants from Eastern Europe (n = 1 study), 66 Asia and Pacific (n = 1 study) 70 and Africa (n = 1 study). 66Intermediate prevalence estimates (2-7%) were found among pregnant migrants from Eastern European (n = 4 studies), 68,70,72,73 Asia and the Pacific (n = 3 studies) 68,72,73 and Africa (n = 4 studies) 62,68,72,73 and low prevalence estimates (<2%) were found among pregnant migrants from Eastern Europe (n = 2 studies), 62,72 Southern Europe (n = 1 study) 62 Asia and the Pacific (n = 1 study) 62 and Latin America and Caribbean (n = 1 study) 62 (Appendix Figure A3, p. 11).

Disease severity/complications
A fifth of CHB-infected pregnant migrants in one study were HBeAg positive, which is associated with more frequent and rapid progression towards severe liver disease and HCC, and an increased likelihood of vertical transmission. 69Most infected pregnant migrants (73.7%) also had detectable HBV DNA, and half had a viral load considered to be associated with chronic liver disease. 69

Factors affecting CHB incidence
Vaccination status and susceptible population.Only one included study explored vaccination coverage in pregnancy.This study focused on women tested for HBV for the first time in the delivery room in a Greek setting, of whom 70.4% were migrants.Low vaccination-induced protection rates (mean 21.4%) were observed among these women who had missed pre-natal HBV maternal testing, but the results for vaccination coverage were not disaggregated by migrant status. 73reening and care pathways.3][74] Foreign citizenship increased the odds of not being screened for HBV by 30% (OR: 1.30, 95% CI: 1.04-1.62) in Italy. 74In Greece, among women who had not had prenatal HBV screening, the majority (70.4%) were migrants, and 5.3% of these were subsequently found to have HBV, a significantly higher proportion than in the comparison group (P < 0.0001). 73onsistent findings were described in a Danish study, 72 where only 43% of pregnant undocumented migrants had a screening result recorded, compared to 99.9% of pregnant people with legal Danish residency. 72Late access to antenatal care was described as an important reason for suboptimal screening coverage by a Danish study, which found that pregnant migrants first accessed antenatal care at a median gestation of 20 weeks (range 6-39 weeks). 63A Finnish study also found that 71% of undocumented migrant pregnant women received inadequate prenatal care, with 61% not receiving any antenatal care in the first trimester and 6% receiving no antenatal care at all. 71his resulted in missed opportunities to prevent mother-to-child transmission of HBV, as demonstrated by an Irish study of HBVinfected children, where 100% of foreign-born and 30% of Irishborn infected children in the study had not received HBIG or HBV vaccine prophylaxis. 46Instances of antiviral treatment not being initiated when indicated and the loss of infected women to follow-up 69,72 were also documented.

Discussion
Our systematic review found intermediate to high CHB prevalence among migrant children in Europe, with a higher prevalence among those originating from the WHO African Region and a higher pooled prevalence among unaccompanied versus accompanied minors.44]49,54 Our data also show that CHB prevalence was significantly higher among migrant pregnant persons compared to the nativeborn pregnant population.Undocumented pregnant migrants, those declaring themselves as UAMs (but not recognised as such by the state) and those originating from Eastern Europe, China and Africa were at particularly high risk of CHB.
6][47][48] Among pregnant migrants, HBeAg positivity and detectable viral loads were reported among a minority of CHB cases, and the reported experience of antiviral use during pregnancy was limited. 37oth migrant children and pregnant persons experience restricted access to healthcare across Europe, leading to a reliance on ad hoc care from NGO-run clinics.This may have contributed to the paucity of data on CHB complications and antiviral use in both groups.Children with CHB are typically asymptomatic but may have high viral loads and HBeAg status, meaning they are at risk of transmission to others and also long-term at risk of developing the sequelae of CHB, such as cirrhosis and HCC in adulthood, leading to an increased risk of mortality, which is known to be significantly higher among migrants with CHB compared to native populations in European host countries. 27The long-term follow-up and monitoring of young people is therefore vital, to allow for the timely commencement of antiviral therapy coupled with regular ageappropriate counselling about viral transmissibility. 27,34Regular follow-up also provides opportunities to prevent transmission by, e.g.vaccinating close contacts. 75mong pregnant migrants, suboptimal antenatal HBV screening due to a lack of access to national pregnancy screening programmes was also reported 72,73 with pregnant undocumented migrants having an even poorer chance of being screened than documented migrants, despite having a higher prevalence of HBV. 73This could possibly lead to cases of preventable vertical HBV transmission. 71,73he WHO proposes that antenatal care, including equal and timely access to HBV screening, should be easily accessible for all migrants, regardless of legal status and ability to pay. 76As part of this, the appropriate administration of antenatal antiviral prophylaxis, plus HBV vaccine and HBIG at birth for the prevention of vertical transmission should be available for all HBV positive migrants.Given the complexities in the supply and availability of these specialist treatments, this needs to be integrated into the regular healthcare system. 77,78However, the reliance on NGOs to fulfil this screening and prevention role for undocumented migrants is a reality in several European countries, leading to frequent loss of follow-up and failure to administer appropriate neonatal prophylaxis to those most at risk. 46,69,72hile specific WHO guidelines exist for the prevention and treatment of CHB in migrant populations through screening, vaccination and equitable access to CHB treatments, 79 ,80 evidence from this review suggests that there is no universal approach to HBV screening in migrant groups across Europe and that policy and practice gaps remain, specifically for children and pregnant migrant groups.Migrants from intermediate-and high-prevalence countries are not always screened, 81 with some countries relying purely on symptom or patient-initiated testing approaches. 82Catch-up immunisation programmes are also not always available in European host countries, 83,84 despite data indicating low HBV vaccination coverage in child migrants, below global and regional average rates.
The strengths of this study include the robust systematic methodology employed, including the meta-analyses and pooled estimates obtained.The inclusion of research studies in all languages also enabled us to capture a wide breadth of literature representative of all of Europe.
Limitations of this systematic review include the fact that most studies were cross-sectional and described the experiences of single centres, the majority of which were specialised migrant health settings.Therefore, the study populations may not necessarily have been representative of all migrant types in the reporting country.There was also a lack of consistency in the terminology used to describe different migrant populations.This has implications in the ascertainment of the true 'at-risk' population when estimating prevalence.In some studies, prevalence estimates in certain migrant groups may have been underestimated due to a lack of comprehensive screening programmes, language and cultural barriers, as well as stigma and discrimination that might have resulted in high-risk migrants not being captured by the studies. 40,64,85The calculation of vaccination coverage also varied between studies, 49,52 and may have been potentially underestimated in cases where anti-HBS was measured prior to booster administration or in cases of co-infection with HIV (where vaccination may not induce an anti-HBS response) or in rare cases of vaccine non-responders. 52It is also worth noting that most studies originated from a small proportion of primarily Western, Northern or Central European countries, and some relied on data over a decade old. 18,27,36,43,46,57,66,70,73,74wo studies carried out in similar geographical regions and time periods may have had some overlapping cases. 67,68Caution should therefore be employed when generalising the findings to wider migrant populations.
The findings of this review highlight the need for several policy and clinical recommendations.First and foremost, national and international European policies should incorporate CHB screening and the provision of robust HBV vaccination programmes for migrant children and pregnant persons.Together, but simultaneously, flexible systems are required to enable opportunistic immunisation while still connecting to central reporting systems to enable follow-up data to be collected.This is supported by evidence that high numbers of migrants are HBV non-immune 86 and that strategies to bolster screening and HBV vaccination efforts in migrant populations in Europe are cost-effective 87,88 and reduce resource impact on healthcare systems. 89hese interventions should be delivered alongside existing preventative health services in maternal and child health so that hepatitis B risk is addressed together with a range of other health inequalities for these populations. 90These should include robust childhood and adolescent catch-up vaccination programmes and antenatal infection screening for the prevention of congenital infections, the latter being in line with the WHO's triple elimination programme, which aims to synergise efforts to eliminate the vertical transmission of HIV, syphilis and HBV.There is a need to capitalise on existing mobile technologies developed during the COVID-19 pandemic to develop digital migrant mobile vaccination and personal health records that are easily accessible to healthcare providers.This would improve the continuum of care for migrants with CHB and improve the efficiency and streamlining of screening procedures. 48uture research should endeavour to optimise the description of the origin of migrants, including their migration status, as well as geographical regions of origin, to facilitate evidence synthesis as well as disaggregation of age.Expansion of the research to include migrants to other high-income and low HBV prevalence contexts, such as North America and Australia, would also provide further relevant context and generalisability.Research on post-arrival transmission of CHB, the ongoing health needs of migrant children and young people living with CHB, as well as qualitative research in the field would provide valuable contextual data for quantitative findings.
Large-scale migration from high-prevalence countries has shifted the HBV landscape in Europe, potentially rendering existing elimination strategies inadequate and allowing at-risk migrant groups to go undiagnosed and untreated. 91Addressing the CHB health needs of child and pregnant migrants in Europe will require further evidence generation and advocacy in order to design equitable non-hostile health policies that are integrated into broader inclusive social policies that are responsive to the changing epidemiology and migrant profiles. 89

Figure 1
Figure 1 PRISMA study selection flow diagram.Adapted from the PRISMA 2020 Statement 28

Figure 2
Figure 2 Number of studies by migrant destination.(N.B.: one study from Luxembourg not visible)

Figure 4
Figure 4 Forest plots of HBV vaccine coverage among migrant children reported by 23 studies.(A) UAM.(B) Other migration status (M, migrants; R, refugees; AS, asylum seekers; IAC, internationally adopted children)

Table 1
Details of all paediatric migrant hepatitis B

Table 1 Continued
a Age is expressed as mean.* = denotes median age.UAM, unaccompanied migrant.VPD, vaccine preventable diseases.

Table 2
Details of all pregnant migrant hepatitis B studies